Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is widely accepted that the cytotoxicity and genotoxicity of benzene results from the action of reactive metabolites. Therefore, genetic variation in metabolic enzyme genes may contribute to susceptibility to chronic benzene poisoning (CBP) in the exposed population. Using a case-control study that included 268 benzene-poisoned patients and 268 workers occupationally exposed to benzene in South China, we aimed to investigate the association between single-nucleotide polymorphisms in genes with phase I and II of metabolism and risk of CBP. The TaqMan technique was used to detect polymorphisms of CYP1A1, CYP1A2, CYP1B1, ADH1B, EPHX1, EPHX2, NQO1, MPO, GSTP1 and UGT1A6 genes. We also explored potential interactions of these polymorphisms with lifestyle factors such as cigarette smoking and alcohol consumption. A weak positive association was found between glutathione S-transferase pi-1 (GSTP1) rs1695 polymorphism and the risk of CBP (P = 0.046), but this association was not statistically significant (P = 0.117) after adjustment for potential confounders. Further analysis showed that the risk of CBP increased in the subjects with EPHX1 GGAC/GAGT diplotype (P = 0.00057) or AGAC/GAGT diplotype (P = 0.00086). In addition, we found that alcohol drinkers with the EPHX1 rs3738047 GA + AA genotypes and non-alcohol drinkers with the GSTP1 rs1695 AA genotype tended to be more susceptible to benzene toxicity. Our results suggest that genetic polymorphisms in EPHX1 may contribute to risk of CBP in a Chinese occupational population.
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PMID:Polymorphisms in phase I and phase II metabolism genes and risk of chronic benzene poisoning in a Chinese occupational population. 1878 59

Human metabolism of benzene involves pathways coded for by polymorphic genes. To determine whether the genotype at these loci might influence susceptibility to the adverse effects of benzene exposure, 208 Bulgarian petrochemical workers and controls, whose exposure to benzene was determined by active personal sampling, were studied. The frequency of DNA single-strand breaks (DNA-SSB) was determined by alkaline elution, and genotype analysis was performed for five metabolic loci. Individuals carrying the NAD(P)H:quinone oxidoreductase 1 (NQO1) variant had significantly twofold increased DNA-SSB levels compared to wild-type individuals. The same result was observed for subjects with microsomal epoxide hydrolase (EPHX) genotypes that predict the fast catalytic phenotype. Deletion of the glutathione S-transferase T1 (GSTT1) gene also showed a consistent quantitative 35-40% rise in DNA-SSB levels. Neither glutathione S-transferase M1 (GSTM1) nor myeloperoxidase (MPO) genetic variants exerted any effect on DNA-SSB levels. Combinations of two genetic polymorphisms showed the same effects on DNA-SSB as expected from the data on single genotypes. The three locus genotype predicted to produce the highest level of toxicity, based on metabolic pathways, produced a significant 5.5-fold higher level of DNA-SSB than did the genotype predicted to yield the least genotoxicity.
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PMID:Genetic susceptibility to benzene toxicity in humans. 1883 23

Bone marrow is a major target of benzene toxicity, and NAD-(P)H:quinone oxidoreductase (NQO1), an enzyme protective against benzene toxicity, is present in human bone marrow endothelial cells, which form the hematopoietic stem cell vascular niche. In this study, we have employed a transformed human bone marrow endothelial cell (TrHBMEC) line to study the adverse effects induced by the benzene metabolite hydroquinone. Hydroquinone inhibited TrHBMEC tube formation at concentrations that were not overtly toxic, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or sulforhodamine B analysis. Hydroquinone was found to up-regulate chondromodulin-I (ChM-I), a protein that promotes chondrocyte growth and inhibits endothelial cell growth and tube formation. Recombinant human ChM-I protein inhibited tube formation in TrHBMECs, suggesting that up-regulation of ChM-I may explain the ability of hydroquinone to inhibit TrHB-MEC tube formation. To explore this possibility further, anti-ChM-I small interfering RNA (siRNA) was used to deplete ChM-I mRNA and protein. Pretreatment with anti-ChM-I siRNA markedly abrogated hydroquinone-induced inhibition of tube formation in TrHBMECs. Overexpression of the protective enzyme NQO1 in TrHBMECs inhibited the up-regulation of ChM-I and abrogated the inhibition of tube formation induced by hydroquinone. In summary, hydroquinone treatment up-regulated ChM-I and inhibited tube formation in TrHBMECs; NQO1 inhibited hydroquinone-induced up-regulation of ChM-I in TrHB-MECs and protected cells from hydroquinone-induced inhibition of tube formation. This study demonstrates that ChM-I up-regulation is one of the underlying mechanisms of inhibition of tube formation and provides a mechanism that may contribute to benzene-induced toxicity at the level of bone marrow endothelium.
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PMID:Benzene metabolite hydroquinone up-regulates chondromodulin-I and inhibits tube formation in human bone marrow endothelial cells. 1952 46

Reactive metabolites formed from benzene include benzene oxide, trans,trans muconaldehyde, quinones, thiol adducts, phenolic metabolites and oxygen radicals. Susceptibility to the toxic effects of benzene has been suggested to occur partly because of polymorphisms in enzymes involved in benzene metabolism which include cytochrome P450 2E1, epoxide hydrolases, myeloperoxidase, glutathione-S-transferases and quinone reductases. However, susceptibility factors not directly linked to benzene metabolism have also been associated with its toxicity and include p53, proteins involved in DNA repair, genomic stability and expression of cytokines and/or cell adhesion molecules. In this work, we examine potential relationships between metabolic and non-metabolic susceptibility factors using the enzyme NAD(P)H:quinone oxidoreductase (NQO1) as an example. NQO1 may also impact pathways in addition to metabolism of quinones due to protein-protein interactions or other mechanisms related to NQO1 activity. NQO1 has been implicated in stabilizing p53 and in maintaining microtubule integrity. Inhibition or knockdown of NQO1 in bone marrow endothelial cells has been found to lead to deficiencies of E-selectin, ICAM-1 and VCAM-1 adhesion molecule expression after TNFalpha stimulation. These examples illustrate how the metabolic susceptibility factor NQO1 may influence non-metabolic susceptibility pathways for benzene toxicity.
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PMID:Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity. 1994 40

Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.
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PMID:Incidence and susceptibility to therapy-related myeloid neoplasms. 2002 17

We have developed a gas chromatography-mass spectrometry method for analysis of benzene (BZ) metabolites in human urine and blood. Here we describe peripheral blood concentrations of hydroquinone (HQ(1)) and catechol (CAT(2)) in total, protein-bound, and unbound (free) forms obtained from BZ-exposed factory workers and controls. Total and unbound metabolites were directly measured in independent experiments, while bound forms were calculated as [total]-[unbound]. In this subset of a larger study, breathing zone benzene, toluene, and xylene were measured for the duration of a workshift, and end-shift blood samples taken from 143 subjects and controls. Potential lifestyle and environmental influences were assessed by questionnaire and bioassay, and single nucleotide polymorphisms in xenobiotic metabolizing enzymes NQO1, MPO, CYP2E1, and GSTT1 were also analyzed for potential contribution to differences in blood metabolite concentration. Total CAT, bound CAT, total HQ, and bound HQ correlated well with benzene exposure, while unbound CAT and HQ displayed no correlation. Nearly all of the metabolites found in blood were bound to protein (CAT 96-99+%, HQ 78-92+%), and when the ratio of bound to unbound metabolites were compared in subsets of exposed workers, the increase in blood metabolite concentration was nearly all due to an increase in the protein-bound molecule. These findings suggest that a threshold for conjugation does not exist within the exposure spectrum studied (0.01-78.8 mg/m(3)). This method demonstrates the feasibility of analyzing benzene metabolites in human blood, and should allow for further investigation of the health effects of benzene and its metabolites.
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PMID:Analysis of hydroquinone and catechol in peripheral blood of benzene-exposed workers. 2002 93

The hematotoxic effects of benzene exposure may be important in the occurrence of subsequent health effects. We sought to provide further information on peripheral blood effects by studying 928 workers in five factories in and around Shanghai, China exposed to a wide range of benzene concentrations. Specifically, we sought to investigate which blood indices are more strongly related to benzene exposure and which concentration levels of benzene result in peripheral blood changes. Lifestyle habits and demographic information was obtained via questionnaire, and potentially important genetic influences were determined by assessing single nucleotide polymorphisms in four genes (NQO1, MPO, CYP2E1, GSTT1). Weekly benzene exposure estimated from individual monitoring results ranged from 0.07 to 872 mg/m(3) with a median value of 7.4 mg/m(3). Twelve peripheral blood indices were examined. Stronger effects on peripheral blood were seen for red cell indices such as anemia and macrocytosis, albeit at higher (>10 ppm) exposure levels. The most sensitive parameters to benzene appeared to be neutrophils and the mean platelet volume (MPV), where effects were seen for benzene air concentrations of 7.8-8.2 ppm. Toluene exposure is a potential confounder for some peripheral blood effects, pointing to the need to scrutinize levels of both compounds in the occupational environment.
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PMID:Peripheral blood effects in benzene-exposed workers. 2003 84

Benzene exposure in occupational settings often occurs with concurrent exposure to toluene, the methyl-substituted derivative of benzene. Toluene is also readily metabolized by CYP450 isozymes although oxidation primarily occurs in the methyl group. While earlier mouse studies addressing co-exposure to benzene and toluene at high concentrations demonstrated a reduction in benzene-induced genotoxicity, we have previously found, using an intermittent exposure regimen with lower concentrations of benzene (50 ppm) and toluene (100 ppm), that toluene enhances benzene-induced clastogenic or aneugenic bone marrow injury in male CD-1 mice with significantly increased CYP2E1, and depleted GSH and GSSG levels. The follow-up study reported here also used the same daily and total co-exposures but over consecutive days and compared the effects of co-exposure on genotoxicity and metabolism in CD-1 mice both with and without buthionine sulfoximine (BSO) treatment to deplete GSH. In this study the toluene co-exposure doubled the genotoxic response (as determined by the erythrocyte micronucleus test) to benzene alone. Further, GSH depletion caused a reduction in this genotoxicity in both benzene exposed and benzene/toluene co-exposed mice. The results are discussed in terms of the analyses of urinary metabolites from this consecutive day study and the intermittent exposure study as well as levels of CYP2E1, epoxide hydrolase, quinone reductase, alcohol dehydrogenase, and aldehyde dehydrogenase activities. The results suggest that the presence of glutathione is necessary for benzene genotoxicity either as a metabolite conjugate or through an indirect mechanism such as TNF-induced apoptosis.
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PMID:Influence of toluene co-exposure on the metabolism and genotoxicity of benzene in mice using continuous and intermittent exposures. 2007 20

This study investigated nucleic acid oxidation associated with exposure to benzene at low levels in 239 workers recruited among traffic policemen, taxi drivers and gasoline pump attendants of the city of Parma (Italy). Biomarkers of exposure, namely urinary t,t-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA), urinary cotinine, and urinary biomarkers of nucleic acid oxidation, namely 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydroguanine (8-oxoGua) were determined by liquid chromatography-tandem mass spectrometry. Relevant polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferases M1-1 (GSTM1), T1-1 (GSTT1), and A1 (GSTA1) were characterized by polymerase chain reaction-based methods in a subgroup of subjects. Biomarkers of nucleic acid oxidation were correlated with each other (r> or =0.32, p<0.0001) and with exposure biomarkers (r> or =0.28, p<0.0001). Multiple linear regression models including age, sex and smoking habits as independent variables demonstrated that benzene exposure is associated with oxidation damage to nucleic acid, particularly to RNA (p<0.0001) and is modulated by the NQO1 polymorphism. The study confirmed a significant modulating effect of GSTM1 (p=0.010), GSTT1 (p=0.023) and GSTA1 (p=0.048) polymorphisms on S-PMA excretion, with a significant interaction between GSTM1 and both GSTT1 and GSTA1 (p=0.006 and p=0.037, respectively).
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PMID:Occupational exposure to low levels of benzene: Biomarkers of exposure and nucleic acid oxidation and their modulation by polymorphic xenobiotic metabolizing enzymes. 2010 May 51

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) is a widely-distributed FAD-dependent flavoprotein that promotes obligatory 2-electron reductions of quinones, quinoneimines, nitroaromatics, and azo dyes, at rates that are comparable with NADH or NADPH. These reductions depress quinone levels and thereby minimize opportunities for generation of reactive oxygen intermediates by redox cycling, and for depletion of intracellular thiol pools. NQO1 is a highly-inducible enzyme that is regulated by the Keap1/Nrf2/ARE pathway. Evidence for the importance of the antioxidant functions of NQO1 in combating oxidative stress is provided by demonstrations that induction of NQO1 levels or their depletion (knockout, or knockdown) are associated with decreased and increased susceptibilities to oxidative stress, respectively. Furthermore, benzene genotoxicity is markedly enhanced when NQO1 activity is compromised. Not surprisingly, human polymorphisms that suppress NQO1 activities are associated with increased predisposition to disease. Recent studies have uncovered protective roles for NQO1 that apparently are unrelated to its enzymatic activities. NQO1 binds to and thereby stabilizes the important tumor suppressor p53 against proteasomal degradation. Indeed, NQO1 appears to regulate the degradative fate of other proteins. These findings suggest that NQO1 may exercise a selective "gatekeeping" role in regulating the proteasomal degradation of specific proteins, thereby broadening the cytoprotective role of NQO1 far beyond its highly effective antioxidant functions.
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PMID:NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. 2036 26


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